The goal of this proposal is to investigate the relationship between direct and indirect DNA damage and the susceptibility of animals to pentachlorophenol (PCP) carcinogenesis. It is hypothesized that animals susceptible to PCP-induced liver tumorigenesis form greater amounts of specific types of DNA damage in the target organ than those of less susceptible animals and that PCP-induced quinones and oxidative stress are the primary mediators for initiating particular types of DNA lesions (i.e. quinone DNA adducts, etheno DNA adducts, 8-oxodeoxyguanosine and apurinic/apyrimidinic sites). Correlation of differential induction of specific types of DNA damage and susceptibility of animals to PCP carcinogenesis will be determined and compared with depletion of glutathione and formation of PCP quinones and lipid peroxidation. The extent of PCP-induced oxidative DNA damage, the formation of other DNA lesions induced by lipid peroxidation, PCP quinone protein and DNA adducts, and apurinic/apyrimidinic will be determined in vivo in rats and mice. In addition, the formation of direct and indirect DNA adducts and the stability of quinone DNA adducts will be determined in vitro.